Environmental agents are believed to be the major cause of cancer in man. This disease should consequently be amenable to control by prevention of either a) exposure to these agents, or b) their carcinogenic action on tissues. Our studies on carcinogenic mechanisms should contribute to this goal by helping to design improved methods for their detection and for inhibiting their carcinogenic action on cells. These objectives are to be realized by extension of our earlier and current studies which attribute a major role to proteases in carcinogenesis and mutagenesis. We have shown that protease inhibitors inhibited tumor promotion and mutagenesis. The inhibition of mutagenesis involves an error-prone DNA repair system that is believed to play an equally critical role in carcinogenesis. This proposal will focus on the role of proteases and the post-replication (error-prone) repair system in the tumor initiation and mutagenic action of 4-nitroquinoline-N-oxide, beta-propiolactone and bis-chloromethyl ether. The latter will be measured by the newly developed simple and rapid alkaline elution assay. Parallel studies on the effects of inhibitors of proteases and DNA repair on initiation, and mutagenesis, and on the kinetics of DNA repair in mouse epidermis and microorganisms will be conducted. These studies should help identify, exploit, and develop protease inhibitors for modifying tumorigenesis.